Rescinnamine-like compounds and a process for producing the same

ABSTRACT

Rescinnamine-like compounds represented by the following formula:   WHEREIN R represents a lower alkyl group; R1 represents a hydrogen atom or a nitro group; R2 and R3 represent a hydrogen atom, a hydroxy, lower alkoxy, aralkyloxy or alkoxycarboxy group; R4 represents a hydrogen atom or a lower alkoxy group; with the proviso that if R1 to R4 are not all hydrogen atoms, or if R1 is not a hydrogen atom and R2 to R4 are not all lower alkoxy groups, then R2 and R3 or R3 and R4 may jointly form an alkylenedioxy group; are prepared by hydrolyzing reserpine, or a derivative thereof, selectively at the 18-position, to form alkylreserpate or a derivative thereof and then reacting said product with cinnamic acid.

United States Patent 1 Kametani Aug. 5, 1975 RESCINNAMINE-LIKE COMPOUNDS AND [73] Assignee: Nippon Chemiphar Co., Ltd.,

Tokyo, Japan [22] Filed: Apr. 19, 1972 [21] Appl. No.: 245,652

[30] Foreign Application Priority Data Oct. 8. l97l Japan 46-78781 Oct. 8. l97l .lapan.... 46-78782 Dec. 28. l97l Japan 46-l05685 [52] US. Cl. 260/240 AL; 424/262; 260/287 A [51] Int. Cl C07d 33/00 [58] Field of Search 260/240 AL. 287 A [56] References Cited UNITED STATES PATENTS 3,109,003 10/1963 Szmuszkovicz et al 260/287 A 3,126,387 3/1964 Robison et al 260/287 A 3,702,325 ll/l972 Fellion 260/240 AL FOREIGN PATENTS OR APPLICATIONS l,40l,524 4/1965 France 260/240 AL OTHER PUBLICATIONS Pelletier, Chemistry of the Alkaloids, frontispage and page 221, Van Nostrand Reinhold Co., Copyright 1970. Klohs, et 21]., J. Am. Chem. Soc., Vol. 76, p. 2843, (1954).

Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Oblon, Fisher, Spivak, McClelland & Maier ABSTRACT Rescinnamine-like compounds represented by the following formula:

N N i 1% 11 R l m COC H: CH

wherein R represents a lower alkyl group; R represents a hydrogen atom or a nitro group; R and R represent a hydrogen atom, a hydroxy, lower alkoxy, aralkyloxy or alkoxycarboxy group; R represents a hydrogen atom or a lower alkoxy group; with the proviso that if R to R are not all hydrogen atoms, or if R is not a hydrogen atom and R to R are not all lower alkoxy groups, then R and R or R and R may jointly form an alkylenedioxy group; are prepared by hydrolyzing reserpine, or a derivative thereof, selectively at the l8-position, to form alkylreserpate or a derivative thereof and then reacting said product with cinnamic acid.

4 Claims, No Drawings RESCINNAMlNE-LIKE COMPOUNDS AND A PROCESS FOR PRODUCING THE SAME BACKGROUND OF THE INVENTION 1. Field of the Invention I This invention relates to novel rescinnamine-like compounds and to an industrially acceptable process for producing the same. This invention further relates to a process for producing an intermediate compound which is useful in the preparation of said rescinnaminelike compounds.

2. Description of the Prior Art Heretofore, it has been known that rescinnamine, ex-

tracted from Rauwolfia serpentina Benth, has a hypotensive effect similar to that of reserpine. Although its sedative effect is weaker, its effect in enhancing myocardial contraction is stronger, and it has fewer contrather of these prior art processes have been sufficient to achieve industrial acceptance.

SUMMARY OF THE INVENTION It is, therefore, one object of this invention to provide a rescinnamine-like compound which is characterized by superior hypotensive effect.

It is another object of this invention to provide an industrial process for advantageously producing said rescinnamine-like compounds.

It is a further object of this invention to provide an industrial process for advantageously producing alkylreserpate or a derivative thereof which is useful as an intermediate in the production of rescinnamine-like compounds.

These and other objects, as will hereinafter become more readily apparent, have been attained by the discovery of compounds having the formula (I):

COCH= CH R indications, such as depression or rhinostenosis than 30 wherein R representsalower alkyl group; R represents reserpine.

Heretofore, alkylreserpate or derivatives thereof, have been produced by simultaneously hydrolyzing a reserpine or a derivative thereof at its 16- and 18- position, and then methylating the obtained product at its l6- position with diazomethane. It has also been reported that such compositions can be obtained by methanolyzing a reserpine or a derivative thereof at the l8-position using methanol as a solvent. However, neia hydrogen atom or a nitro group; R and R represent hydrogen, hydroxy, lower alkoxy, aralkyloxy or alkoxycarboxy; R represents hydrogen or lower alkoxy; or R and R or R and R may jointly form an alkylene- 35 dioxy group; except when R, to R are all hydrogen atoms or R, is a hydrogen atom and R to R are all lower alkoxy groups.

According to the present invention, rescinnaminelike compounds are produced as follows:

ooc 0R R (11) OR I\ ll l III/ H OR R4 HOOCHC=HC s DETAILED DESCRIPTION OF THE INVENTION It has now been found that when the reserpine or its derivatives are treated by alkaline reagent in the presence of mixed solvents of lower alcohol and cyclic ether, the l8-position thereof are only hydrolyzed advantageously selectively to obtain the alkyl reserpate or its derivatives.

In carrying out the process of the present invention, metallic sodium, metallic potassium, or the like is dissolved in a lower alcohol, such as methanol or ethanol,

Alternatively, the compounds represented by R or R may be a hydroxy group in the formula (I), produced by hydrolyzing the corresponding lower alkoxycarboxy substituted compound.

This hydrolysis can be conducted as follows: Metallic sodium is dissolved in a lower alcohol such as, for example, methanol or ethanol, and water and an organic solvent, such as dioxane, tetrahydrofuran, etc. is added thereto. The corresponding lower alkoxycarboxy substituted compound is added to the mixture, and the mixture is stirred at room temperature, or is heated for approximately 2 hours. The resulting hydroxyl substituted compounds may be isolated or refined by normal procedures.

The hypotensive effect of the rescinnamine-like compounds was compared with rescinnamine by cannulation in unanesthetized, spontaneously hypertensive rats. After intravenous injection of the compounds to 3 rats in one group, the ratio of hypotensive effect for 5 hours was calculated as ED The ED value was calculated by a dose-response regression line. The effect of the rescinnaminelike compound in decreasing systemic blood pressure is shown in the following Table I:

and water and cyclic ether, such as dioxane or tetrahydrofuran, etc. is added thereto. Then, the reserpine or a derivative thereof is added to the mixture and reacted. The reaction is preferably conducted at room temperature by stirring for 20 to hours, but the reaction may be conducted by heating under reflux for 2 to 5 hours.

When thus reacted, the reserpine, or the derivative thereof, is selectively hydrolyzed at its l8-position to provide an alkylreserpate or a derivative thereof. This alkylreserpate or derivative is dissolved in a solvent such as pyridine, etc., and a cinnamic acid or a reactive derivative thereof of the formula (IV), is added thereto and reacted. Although the reaction is conducted at room temperature, the reaction may be accelerated by application of heat. The reactants are stirred and the reaction reaches completion within 20 to 30 hours.

Suitable reactive derivatives of cinnamic acid which may be used in this reaction include the acid halides, mixed anhydrides, active esters or anhydrides.

When the reactive solution thus obtained is poured, for example, into ice water, and is acidified with acid such as dilute hydrochloric acid, etc., and isolated by conventional refining procedures, rescinnaminelike compounds are produced.

Having generally described the invention, a further understanding can be obtained by reference to certain specific Examples which are provided herein for purposes of illustration only and are not intended to be construed as limiting unless otherwise specified.

EXAMPLE 1 0.34 g. of metal sodium was dissolved in 300 ml. of anhydrous methanol, 0.27 g. of water and ml. of tetrahydrofuran were added thereto, and 5 g. of reserpine hydrochloride was further added thereto. After the mixture was stirred at room temperature for one day, the solvent was evaporated. When the residue was dissolved in chloroform, washed with aqueous solution of saturated sodium bicarbonate, and then with water, dried over sodium sulfate and the solvent was evaporated therefrom, there was obtained a pale yellow solid. When this was recrystallized from methanol, there was obtained 2.87 g. (93% of yield) of methylreserpate as colorless needles having a melting point of 233 to 239C.

EXAMPLE 2 2 g. of 3,4-dimethoxycinnamic acid was suspended in 20 ml. of benzene, 2 ml. of thionyl chloride was added thereto, and the mixture was heated under reflux on a conditions except that chloroform-hexane was used as water bath for 3 hours. Then, when the excessive thiothe solvent of recrystallization, and there was obtained nyl chloride and benzene were evaporated under re- 0.56 g. (75% of yield) of methylreserpate 3-methoxyduced pressure, there was obtained a colorless solid of 4'-ethoxycinnamate, represented by the following for the corresponding cinnamoyl chloride. 5 mula and characterized as a pale yellow powder having After this cinnamoyl chloride was dissolved in 30 ml. a melting point of 140 to 141C.:

1 1 H C I OOCHC=HC H H cooo 2 5 OCI-I OCH of benzene, this mixture was added to a solution of 1 EXAMPLE 4 g. of methylreserpate in 30 ml. of pyridine, and the mixture was allowed to stand at room temperature for one day while being occasionally stirred. The mixture was poured into 100 ml. of ice water. Then, the mixture was made acidic with dilute hydrochloric acid, and ex- Using 1.2 g of methylreserpate and cinnamoyl chloride, produced by the procedure of Example 2, under the same reaction conditions, from 2 g. of 2-nitro- 3,4,5-trimethoxycinnamic acid, the same procedure of Example 2 was repeated under the same reaction contracted with chloroform. The chloroform layer was ditions, and there was then obtained 1 5 7% of washed with saturated sodium bicarbonate, dried over i ld) f methylreserpate 2' i 3',4',5' i h sodium sulfate, and evaporated to obtain a brown ycinnamate represented b th f llo i g f r la amorphous matter. After this was stimulated with which was characterized as a pale yellow powder havether, it was recrystallized from benzenehexane, and ing a melting point of 141 to 143C.:

OOCHC=HC OCH No ocH there was obtained 0.81 g. of yield) of methylres- EXAMPLE 5 erpate 3',4'-dimethoxycinnamate, represented by the 45 following formula, which was characterized as a pale Using 1.8 g. of methylreserpate and cinnamoyl chloyellow powder, having a melting point of 180 to ride produced by the procedure of Example 2 under 181C. the same reaction conditions, from 2 g. of 3- N H CO HsCOOC OOCHC=HC ;OCH

OCH OCH 3 EXAMPLE 3 ethoxycarb0xy-4-methoxycinnamic acid, the same procedure of Example 2 was repeated under the same re- Using 0.5 g. of methylreserpate and cinnamoyl chloaction conditions, and there was then obtained 1.6 g. ride, produced by the procedure of Example 2, under 6 0f yi l of hylr s p h xy arboxythe same reaction conditions, from 1.5 g. of 4'-methoxycinnamate represented by the following for- 3-methoxy-4-ethoxycinnamic acid, the same procedure mula which was characterized as a pale yellow powder of Example 2 was repeated under the same reaction having a melting point of 119 to 121C:

EXAMPLE 6 Using 1.5 g. of methylreserpate and cinnamoyl chloride produced by the procedure of Example 2 repeated under the same reaction conditions from 3 g. of 3- methoxy-4-ethoxycarboxycinnamic acid, the same procedure of Example 2 was repeated under the same reaction conditions, and there was then obtained 1.0 g. (74% of yield) of methylreserpate 3'-methoxy-4'- ethoxycarboxycinnamate represented by the following formula which was characterized as a pale yellow pow- H COOC CH O EXAMPLE 7 2 g. of 3,4-methylenedioxycinnamic acid was suspended in 30 ml. of benzene, 2 ml. of thionyl chloride was added thereto, and the mixture was heated under reflux in a water bath for 3 hours. The excessive thionyl chloride and benzene were evaporated under reduced pressure, and hexane was added thereto. The mixture was then again evaporated, and there was obtained a white solid identified as 3,4-methylenedioxycinnamoyl chloride.

Cinnamic chloride was then dissolved in 30 ml. of 65 benzene, and a solution of 2 g. of methylreserpate in 30 ml. of pyridine was added thereto. The mixture was allowed to stand at room temperature for one day while OOCHC=HC OCH3 ocooc n OOCHC=HC -Q 2 OCH the following formula, which was characterized as a grey powder having a melting point of 210 to 210.5C.:

CH OO OCOCH=CH Q OCH Elemental Analysis: as C H O N Calculated Found umax 3425 (lndole NH).

1700(COO) 2.35 (1H. d. J lHz, CH =Q Ar) 3.99 (2H. s, methylenedioxy) 5.52 (1H, m. 3 H) EXAMPLE 8 -Continued Using 1.3 g. of methylreserpate and cinnamoyl chlo- 555 (H m 3 H) ride, produced by the procedure of Example 7, under 6.15 (6H: 5,2 X OCH) the same reaction conditions, from 2 g. of 6-nitro-3,4- (314 17 OCHs) methylenedioxycinnamic acid, the same procedure of 5 Example 7 was repeated under the same reaction conditions. 1.42 g. (71% of yield) of methylreserpate 6'- nitro-3, 4'-methylenedioxycinnamate, represented by EXAMPLE 9 the following formula, was obtained, which was charac- 2 g. of 3-benzyloxy-4-methoxycinnamic acid obterized as a grey powder having a melting point of 213 10 tained by reacting 3-benzyloxy-4- to 214C. (decomposition). v methoxybenzaldehyde with malonic acid was reacted CH ooc OCH=CH' i: Y

i O OCH Elemental Analysis: as C H O N with thionyl chloride under the same reaction condi- 25 tions as in Example 7 to obtain the corresponding cinnamoyl chloride. The thus obtained cinnamoyl chloride Calculated 2 v i was reacted with g. of methylreserpate under the Found 70); 62.60 5.17 6.56 same reaction conditions as in Example 7, and the product was chromatographed over neutral alumina, IR m 30 and eluted with chloroform-benzene (1 1). The elute vmax 3425 (lndole NH) was evaporated and the residue was recrystallized from 1;; chloroform-hexane and there was obtained 1.39 g. [570 and 330 (C N02), (58%) of methylreserpatc 3-benzyloxy-4'- NMR (CDCl +sligl 1tDMSO-d )I methoxycmnamate represented by the following for- 0.32 (1H. m, "5101c NH) 5 mula, which was characterized as pale yellow needles 1.74(lH,d.J-l6HzCHfi-Ar) o o 3 (1H. d 1652, 95 CH n having a melting pomt of to 171.5 C. (decomposi- 3.78 (2H, s. methylenedioxy) tio Elemental Analysis: as C H O N C H N Calculated (70) 70.59 6.47 4.12

Found ('70) 70.59 6.20 4.26

CHC]. IR 3 cm Vmx.

3425 (Indole NH) 4.88 (2H, s, on

5.62 (1H, m, 3- H) 6.22 (6H, s, 2 XOCH 6.50 (3H, s, '17 OCH EXAMPLE 1O 2 g. of 2-nitro-4-benzyloxy-3,S-dimethoxycinnamic acid, obtained by reacting 2-nitro-4-benzyloxy-3,5- dimethoxybenzaldehyde with malonic acid, was reacted with thionyl chloride under the same reaction conditions as in Example 7 to obtain the corresponding cinnamoyl chloride. The thus obtained cinnamoyl chloride was reacted with 0.64 g. of methylreserpate under Elemental Analysis Calculated (70) Found CHCl IR 16 Hz, on CH- Ar) the same reaction conditions as in Example 7, and the product was chromatographed over neutral alumina, and eluted with chloroform-benzene, (l l). The elute was evaporated and the residue was recrystallized from chloroformhexane so that there was obtained 0.96 g. (82% of yield) of methylreserpate 2-nitro-4- benzyloxy-3,5-dimethoxycinnamate represented by the following formula, which was characterized as a brown powder having a melting point of to l3l.5C.:

OCOCH CH 3 No H as C I'I O1 N C H N Continued 2.18 1 H, d, CH 1 CE- Ar) 3.62 (1H, d, c5 =Cl-l-Ar) 5.65 (1H, m, 3 H) 6.07 (6H, s, 2 X OCT-I 6.17 (6H, s, 2 X OCT-l3) 6.48 (3H, s, 17 OCH EXAMPLE ll acetic acid was added thereto, and the solvent was 40 evaporated. The residue was extracted with chloro- 28 mg. of metal sodium was dissolved in 25 ml. of anform, and the extract was washed with saturated s0- hydrous methanol, and one droplet of water was added dium bicarbonate solution and then with water. The thereto, and 800 mg. of methylreserpate 3- chloroform layer was dried over sodium sulfate, and cthoxycarboxy-4-methoxycinnamate in 25 ml. of tetthe solvent was evaporated, so that there was obtained rahydrofuran was added thereto. The mixture was then 45 a brown amorphous matter. This was recrystallized stirred at room temperature for 2 hours. One drop of from chloroformhexane, and there was then obtained 450 mg. (64% of yield) of methylreserpate 3'-hydroxy- EXAMPLE 4'-methoxycinnamate represented by the following for- Using 1.5 g. of methylreserpate 3'-meth0xy-4- mula, which was characterized as a pale yellow powder ethoxycarboxycinnamate, the same procedure of Exhaving a melting point of 162 to 164C: ample l l was repeated under the same reaction condil l6 tions, and there was obtained 1.0 g. (78% of yield) of methylreserpate 3'-methoxy-4'-hydroxycinnamate repl 'i P resented by the following formula, which was charac- HO v terized as pale yellow needles having a melting point of H /L\ 259 to 260C: 5 HOOC f. OQOCH=CH 3 OR R2 l 1! I H 00 T l l w. l 1 H 300 OOCHC HC J W OH ocn *OCH Having now fully described the invention, it will be wherein R represents lower alkyl; R and R each repreapparent to one of ordinary skill in the art that many sent hydrogen, hydroxy, lower alkoxy, benzyloxy or alchanges and modifications can be made thereto withkoxycarboyx; R represents hydrogen or lower alkoxy; out departing from the spirit or scope of the invention or R and R taken together or R and R taken together as set forth herein. Accordingly, may jointly form a methylenedioxy group.

What is claimed and desired to be secured by Letters 3. Methylreserpate 2'-nitro-3',4',5'-trimethoxycin- Patent is: namate. I

I I I 4. Methylreserpate 3-methoxy-4- l. Methylreserpate 3 ,4 -dlmethoxyc1nnamate. hydroxycinnamate 2. A compound of the formula: 

1. METHYLRESERPATE 3'', 4''-DIMETHOXYCINNAMATE.
 2. A compound of the formula:
 3. Methylreserpate 2''-nitro-3'',4'',5''-trimethoxycinnamate.
 4. Methylreserpate 3''-methoxy-4''-hydroxycinnamate. 